Dysregulation of Iron Metabolism in Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis

Dysregulation of iron metabolism has been observed in patients with neurodegenerative diseases (NDs). Utilization of several importers and exporters for iron transport in brain cells helps maintain iron homeostasis. Dysregulation of iron homeostasis leads to the production of neurotoxic substances and reactive oxygen species, resulting in iron-induced oxidative stress. In Alzheimer's disease (AD) and Parkinson's disease (PD), circumstantial evidence has shown that dysregulation of brain iron homeostasis leads to abnormal iron accumulation. Several genetic studies have revealed mutations in genes associated with increased iron uptake, increased oxidative stress, and an altered inflammatory response in amyotrophic lateral sclerosis (ALS). Here, we review the recent findings on brain iron metabolism in common NDs, such as AD, PD, and ALS. We also summarize the conventional and novel types of iron chelators, which can successfully decrease excess iron accumulation in brain lesions. For example, iron-chelating drugs have neuroprotective effects, preventing neural apoptosis, and activate cellular protective pathways against oxidative stress. Glial cells also protect neurons by secreting antioxidants and antiapoptotic substances. These new findings of experimental and clinical studies may provide a scientific foundation for advances in drug development for NDs

Microtubule Dynamics Regulate Cyclic Stretch-Induced Cell Alignment in Human Airway Smooth Muscle Cells

Microtubules are structural components of the cytoskeleton that determine cell shape, polarity, and motility in cooperation with the actin filaments. In order to determine the role of microtubules in cell alignment, human airway smooth muscle cells were exposed to cyclic uniaxial stretch. Human airway smooth muscle cells, cultured on type I collagen-coated elastic silicone membranes, were stretched uniaxially (20% in strain, 30 cycles/min) for 2 h. The population of airway smooth muscle cells which were originally oriented randomly aligned near perpendicular to the stretch axis in a time-dependent manner. However, when the cells treated with microtubule disruptors, nocodazole and colchicine, were subjected to the same cyclic uniaxial stretch, the cells failed to align. Lack of alignment was also observed for airway smooth muscle cells treated with a microtubule stabilizer, paclitaxel. To understand the intracellular mechanisms involved, we developed a computational model in which microtubule polymerization and attachment to focal adhesions were regulated by the preexisting tensile stress, pre-stress, on actin stress fibers. We demonstrate that microtubules play a central role in cell re-orientation when cells experience cyclic uniaxial stretching. Our findings further suggest that cell alignment and cytoskeletal reorganization in response to cyclic stretch results from the ability of the microtubule-stress fiber assembly to maintain a homeostatic strain on the stress fiber at focal adhesions. The mechanism of stretch-induced alignment we uncovered is likely involved in various airway functions as well as in the pathophysiology of airway remodeling in asthma

Three Cases of Bronchial Asthma Preceding IgG4-Related Autoimmune Pancreatitis

Background: Autoimmune pancreatitis is characterized by diffuse swelling of the pancreas and a high serum immunoglobulin (Ig) G4 concentration. Histopathologically, dense infiltration of lymphocytes and IgG4-positive plasma cells with fibrosis are seen in the pancreas. Although allergic diseases complicating autoimmune pancreatitis have been reported, the clinical features of bronchial asthma complicated by autoimmune pancreatitis remain unclear. Case Summary: We report three cases of bronchial asthma preceding the onset of type 1 autoimmune pancreatitis by 3 months to 30 years. All three cases were males with high serum IgG, IgG4, and IgE concentrations. The radioallergosorbent tests were positive for common allergens such as mites and house dust. One case had a pulmonary manifestation that proved to be an inflammatory pseudotumor of the lung with an accumulation of IgG4-positive plasma cells. The asthma symptom was ameliorated by oral prednisolone therapy for autoimmune pancreatitis, and when the corticosteroid doses were reduced, asthma became worse in all three cases. Discussion: It is possible that atopy and increased Th2 cell activity are related to a higher coincidence of IgG4-related diseases such as type 1 autoimmune pancreatitis. Because the present cases are few in number, further studies are necessary

A combination therapy for Kawasaki disease with severe complications: a case report

Kawasaki disease (KD) is a form of acute multisystem vasculitis that presents with various complications, including coronary artery aneurysm. Heart failure and brain damage are rare, but life-threatening complications are associated with KD. Here, we describe a 4-year-old girl who developed intravenous immunoglobulin-resistant KD with both left ventricular failure and acute encephalopathy. On day 8 of the illness, the low left ventricular ejection fraction, mitral regurgitation, and low blood pressure, which required continuous administration of dobutamine, were observed during the treatments for KD, including intravenous immunoglobulin. She also appeared unconscious, where the electroencephalogram showed slow waves of activity in all regions of the brain. The cardiac performance improved after she received plasma exchange for three days. However, her unconsciousness with slow waves of activity on electroencephalogram and fever continued after the plasma exchange. Therefore, she was treated with methylprednisolone pulse, followed by prednisolone, as well as intravenous immunoglobulin. Finally, she recovered without any cardiac or neurological sequelae not only at the time she was discharged, but also throughout the follow-up period. The combination therapy using plasma exchange and methylprednisolone pulse may be a treatment option for severe KD with left ventricular failure and acute encephalopathy complications